Production of quinoline derivatives



Patented May 5, 1931 stares PATENT SGHERING-KQELBAUIIC AKTIEIIGESELLSCHAFT, OF BERLIN, GERMANY PRODUCTION OF QUINOLINE DERIVATIVES J can be obtained more smoothly and in better yield if alkyl-B-halogen ethyl ketones, prepared for instance by causing ethylene to act on anacyl halogenide in the presence of a catalyst and treating the reaction product with water, as described in an application for patent of the United States Serial No. 240,612 executed on November 29, 1927, by lValter Schoeller and myself, are subjected to condensation with aniline or its derivatives in a watery acid solution in the pres ence of an oxidizing agent, for instance nitrobenzene or arsenic acid. I have found that the reaction will take place also in neutral and in an alkaline solution and even without the addition of an oxidizing agent as follows:

, +R.OO.CH2.CH2C1 +Ho1+m0+m NH: 7 N I Exampie 1.4-methyl guinoline (lepidine) 93 parts by weight methyl-,B-chloroethyl ketone are mixed with 80 parts aniline, 350

parts concentrated hydrochloric acid or the I corresponding quantity of a 40 per cent sulfuric acid and 70 parts nitrobenzene. The mixture is heated for some hours on a water bath, whereupon the nitrobenzene is removed by extraction with ether or by distillation with steam. From the resulting liquid, upon it being rendered alkaline, there is extracted by ether a basic mixture, from which after distillation of the ether and dissolution with a small quantity of alcohol an alcoholic solution of pic'ric acid will precipitate a large quantity of lepidine picrate. In order to recover the free base, the solution is rendered I alkaline and lepidinev is driven over with N0 Drawing. Application. filed January 11, 1928, Serial No. 246,086, and in Germany January 14, 1927.

steam. The 4-methyl tained has the formula Ewample 2.6'-met7towy lepidine Equal parts by weight of p-anisidine, nitrobenzene, methyl chlorethyl ketone and the five-fold quantity of concentrated hydrochloric acid are mixed and the mixture heated for some time on the water bath to render the reaction complete. The product of reaction is treated further as described with reference to Example 1. The separation of the bases in the mixture can also be efi'ected in such manner that the anisidine, which has not been consumed in the reaction, is changed by acetylizing or diazotizing and boiling, whereupon p-methoxy lepidine can be separated in the usual manner.

Instead of nitrobenzene I can also use arsenic acid. r

The p-methoxy lepidine has the formula N Ewa mple 3.8-met7wmg lepidine ored at this temperature. The 8-methoxy lepidine has the formula quinoline which is 0b- This compound is obtained from p-phenetidine in the manner described with reference to Examples 2 and 3. It has the formula N E wample 5.6-m'tr0 lepicliae 58 parts by weight of p-nitroaniline, 175 parts concentrated hydrochloric acid, 35 parts nitrobenzene and as parts methyl-B- chloroethyl ketone are heated on the water bath during some hours. After expulsion of the nitrobenzene by means of steam the liquid is rendered alkaline and the precipitate, which has formed, is removed by suction. After extraction with hot alcohol the alcoholic solution is treated with alcoholic picric acid for the recovery of the picrate. The picrate is decomposed with concentrated hydrochloric acid and water, the picric acid is removed by extraction with ether, and the base is recovered from the hydrochloric acid solution, after the same has been rendered alkaline, by extraction with ether. lhe hitherto unknown G-nitrolepidine which results in this treatment is a crystallized compound which, on being repeatedly recrystallized from alcohol, melts at 137 C. It has the formula 7 This compound is obtained by treating pchloroaniline as described with reference to Examples 2 and 3. T he picrate melts at 222 C. The hitherto unknown fi-chloro lepidine is a crystallized compound melting at 71/72 C. and being readily soluble in the usual organic solvents. It has the formula Example 7.Lepz'(line-8-carb acrylic acid I parts by weight of anthranilic acid ester, 175 parts concentrated hydrochloric acid, 35 parts nitrobenzene and 50 parts methyl-flchloroethyl ketone are heated during hours on the water bath. The nitrobenzene is removed from the reaction liquid by extraction with ether and the acid liquid is boiled during three hours under the reflux condenser in order to saponify the esters present therein. Thereupon the liquid is acidified by means of a solution of sodium acetate, and

such oil, as may have separated out is removed by shaking with ether. In the watery part of the liquid needles segregate out, which are obtained by sucking the liquid off and form lepidine-8-carboxylic acid. This compound is soluble in boiling water and alcohol, cold acetone and caustic alkali, insoluble in ether and, on being repeatedy recrystallized from water, melts at 186187 C. It has the formula OgH Example 8 52 parts by weight anisidine, 100 parts alcohol (96 per cent), 35 parts nitrobenzene, 50 parts concentrated caustic soda solution and 46 parts methyl-fl-chloro ethyl ketone are stirred some time at ordinary temperature, whereupon the mixture is heated during one hour on the water bath and the alcohol is driven over. To the liquid is added hydrochloric acid to obtain an acid reaction with congo, whereupon the nitrobenzene is driven over with steam, the filtered residue is rendered alkaline and is extracted with ether. The ether now contains a mixture of bases from which the picrate of p-methoxy lepidine can be recovered as described above. It has the formula CHQO Example 9.4-ethyl guinolz'ne This compound can be obtained from ethyl-B-chloroethyl ketone and aniline in a manner analogous to the one described with reference to lepidine. Its picrate melts at 195 (1, being dark colored at that temperature. The base itself is oily, has a smell resembling that of quinoline, and is volatile with steam. It has the formula In the claims affixed to this specification the term 'alkyl quinolines is intended to include also derivatives of the alkyl quinolihe, the benzene nucleus of which includes substituents, for instance the chlorine atom, the nitro, carboxyl-, or methoxy-group, and in consequence thereof an aniline is intended to include also the derivatives thereof, such as for instance chloroaniline, i1itroaniline,anthranilic acid or esters of amino phenol.

Various changes may be made in the details disclosed in the foregoing specification without departing from theinvention or sacrificingthe advantages thereof.

Iclaim: A 1. The process of producing a-alkyl quinolines having the formula I N X4 wherein R is analkyl, while X X X X are hydrogen atoms or any univalent substituents, comprising reacting with an alkyl- B-halogen ethyl ketone in watery solution on an aniline and isolating the resulting alkyl quinoline.

2; The process of producing l-alkyl quinolines having the formula wherein R is an alkyl, while X X X K are hydrogen atoms or any univalent substituents, comp-rising reacting with an alkyl- B-halogen ethyl ketone in watery acid solution on an aniline andisolating the resulting alkyl quinoline.-

3. The process of producing et-alkylquinolines having the formula wherein R is an alkyl, while X X X X are hydrogen atoms or any univalentsub- ;tituents, comprising reacting with an alkylo ,B-halogen ethyl ketone in watery solution on an anihne 1n the presence of an oxidizing agent and isolating the resulting alkyl quinoline. V

' 4."The process of producing l-alkyl quinolines having the formula wherein R is an alkyl, while X X X X are hydrogen atoms or any univalent substituents, comprising reacting with an alkyl- B-halogen ethyl ketone in acid watery solution on an aniline in the presence of an oxidizing agent and isolating the resulting alkyl quinoline.

5. The process of producing4-alkyl quinoline having the formula r V X4 4 wherein R is an alkyl, while X X X X are hydrogen atoms or any univalent substituents, comprising reacting with an alkyl- (i-halogen ethyl ketone inwatery solution on an aniline in the presence of nitrobenzene and isolating the resulting alkyl quinoline.

6. The process of producing et-alkyl quinolines having the formula wherein R and R are the same or different alkyl groups, comprising acting with an alkyl-B-halogen-ethyl ketone on an alkyl ester 1 of amino phenol and isolating the resulting 6-alkoxyl-alkyl quinoline.

8. The process of producing G-methox'y lepidine having the formula CiHa Oligom comprising acting with a methyl halogen ethyl ketone on p-anisidine and isolating the resulting 6-methoxy lepidine.

9. The process of vproducing .6-methoxy lepidine, having the formula a on o N comprising acting with. a methyl halogen ethyl ketone in watery solution on p-anisidine and isolating the resulting p-methoxy lepidine.fl i

-10. The process of producing G-methoxy lepidine having the formula comprising acting With a methyl halogen ethyl ketone in Watery acid solution on panisidine and isolating the resulting pni'ethoXy lepidine. v r V 11;. The process of producing 6-methoiz'y lepidine having the formula (ERGO comprising acting with a-niethyl halogen ethyl ketone on p-anisidine in the presence of an oxidizing agent and isolating the re sulting p-methoXy lepidine.

12. The process of producing G-methoxy lepidine having the formula omoO comprising acting with a methyl halogen ethyl ketone in "p-ahisidine in the presence of nitrobenzene and isolating the resulting p-methoxy lepidine.

13. The process of producing G-methoxy lepidine having the formula comprising acting with a methyl halogen ethyl ketone inw'atery solutionon'p-anisidine in the presence of nitroben'zeneand isolating the resulting p methoxy lepidine.

14. The process of producing G-methoxy lepidine having the formula comprising acting with a inetliyl chloro ethyl ketone on p-anisidine and isolating the resulting 6-methoxylepidine.

15. The process of producing G-methoxy lepidine having the formula comprising acting With a methyl chloro ethyl ketone in watery solution on p-anisidine and isolating the resulting p-methoxy lepidine.

16. The process of producing 6-metlioxy lepidine having the formula comprising acting With a methyl chloro ethyl ketone in Watery acid solution on p-anisidine and isolating the resulting p-methoxy lepidine.

17. The process of producing 6-metho'xy lepidine having the formula ongo comprising acting with a methyl chloro ethyl ketone in Watery solution on p-anisidine in the presence of nitr'ohenze'ne and isolating the resulting p-metlioxy lepidine.

'In' testimony 'vvhereof I aiii'x my signature.

CLEMENS ZOLLNER. 

